Project Summary Amnestic mild cognitive impairment (aMCI) is a pre-dementia stage of Alzheimer?s disease that is characterized by declines in episodic memory, and is often accompanied by beta-amyloid load, which plays a role in the pathogenesis of Alzheimer?s disease. As the population of older adults continues to grow, it becomes more imperative to understand what measures may be taken in order to minimize the concomitant growth of the aMCI and Alzheimer?s disease populations. Previous research in 5XFAD mice, a well-established model of Alzheimer?s disease, has demonstrated that 40 Hz (gamma band) neural entrainment can reduce beta-amyloid load in the neural regions where entrainment occurs. Here, we propose to replicate and extend these findings regarding the therapeutic potential of neural entrainment and assess the feasibility of translating this animal-based research to aMCI patients. To achieve this, we propose two experiments. The first experiment will use 40 Hz alternating current stimulation to entrain multiple cortical regions simultaneously in 5XFAD mice to reduce beta-amyloid load more globally than prior research. Furthermore, we will parametrically manipulate stimulation intensity to identify the optimal current that reduces beta-amyloid load. Whereas beta-amyloid load will serve as the primary outcome measure, episodic memory performance will serve as a secondary outcome measure. The second experiment will apply the optimal current intensity from experiment 1 in patients with aMCI via transcranial alternating current stimulation (tACS). Our primary outcome measures are concerned with the safety and tolerability of this method: skin redness under the electrodes, burning sensations, headache, scalp pain, back pain, neck pain, dizziness, tingling, itching, sleepiness, trouble concentrating, acute mood change, phosphenes and seizure. Secondary outcome measures include beta- amyloid load as assessed by positron emission tomography and episodic memory performance. For both experiments, stimulation will be applied for one hour on five consecutive days (Monday through Friday), followed by one hour of stimulation on each of the three following Mondays for a total of eight stimulation sessions over a one month period. Tests of episodic memory as well as beta-amyloid load will be measured pre- and post-stimulation (at the end of one month). Importantly, feasibility of tACS in aMCI patients will be continuously assessed during each stimulation session via observational data and patient feedback. The outcome of this research will advance our knowledge of the therapeutic potential of neural entrainment in a mouse model of Alzheimer?s disease and provide a critical feasibility assessment for the potential to rapidly translate animal research to human therapeutics. If tACS proves to be safe and tolerable in aMCI patients, this will facilitate future research to deploy randomized controlled trials to assess efficacy of this approach.